other tissues. It is also unclear whether the strong quantitative relationship between subjective social isolation and leukocyte transcriptional profiles observed here stems from a causal effect of social processes on gene expression (for example, via the neuroendocrine system), or whether differential gene expression in the immune system might instead drive variations in social behavior (for example, via effects of pro-inflammatory cytokines and prostaglandins on central nervous system function) [50]. The effects of acute 'sickness behavior' are unlikely to explain the present results because this study analyzed long-term individual differences in experienced loneliness (that is, consistently expressed over at least three years). However, longitudinal studies will be required to rule out the possibility that variations in chronic inflammation might potentially influence long-term individual differences in social behavior. This study's identification of a plausible neuroendocrine mediator of transcriptional alteration (GR signaling), which is known to relate to social phenotype in humans [27-30] and is causally impacted by experimental social isolation in animal models [11-14], is consistent with social influences on gene expression. Experimental manipulations of long term social behavior may ultimately be required to definitively establish causation in the human clinical setting. What is clear from this study's ancillary analyses is that
